Expedient synthesis of oseltamivir and related compounds via direct olefin diazidation-diamidation reaction

ABSTRACT

Disclosed herein are improved methods for the preparation of oseltamivir, and intermediates useful thereto.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation-in-part of U.S. application Ser. No.15/938,204, filed on Mar. 28, 2018, the contents of which are herebyincorporated in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant No. GM110382awarded by the National Institutes of Health. The government has certainrights in the invention.

FIELD OF THE INVENTION

The invention is directed to improved new methods for obtainingoseltamivir from readily available commodity chemicals via a late-stagedirect olefin diazidation-diamination reaction.

BACKGROUND

Oseltamivir phosphate, marketed by Roche under the brand name Tamiflu®,is an antiviral medication that is used to treat and prevent influenza Aand influenza B (flu). It is recommended for people who havecomplications or are at high risk of complications within 48 hours offirst symptoms of infection. Given the severe flu pandemics in 2009-2010and in 2017-2018, there is a high demand for the development of evenmore robust and economical production routes of Tamiflu®.

Many current production routes rely on expensive shikimic acid (currentcost is approximately $109/gram) as the starting material. The reportedoverall yield in one disclosed 12-step synthetic route is about 16.5%.Among these steps, at least four steps involve either cryogenic cooling(−34° C.) or heating (>60° C.). Since the development of Roche'sTamiflu® synthesis, a range of syntheses of Tamiflu® have been developedin academic labs; however, it is not believed that any of them have beencommercialized in the US.

There remains a need for oseltamivir production routes that neitherinvolve the usage of expensive starting materials like shikimic acid norinvolve tedious synthetic steps, especially those are related theinstallation of two nitrogen-based groups.

SUMMARY

Disclosed herein are a range of new synthetic routes for oseltamivir anduseful intermediates thereto. A key transformation of these improved newprocesses is the direct catalytic and stereoselective olefin diazidationof a highly functionalized synthetic intermediate to afford thetrans-vicinal diamino moiety present in oseltamivir. The details of oneor more embodiments are set forth in the descriptions below. Otherfeatures, objects, and advantages will be apparent from the descriptionand from the claims.

BRIEF DESCRIPTION OF THE FIGURE

The FIGURE depicts an embodiment of an inventive synthetic sequence,wherein R¹, R², R³, R^(h), and R^(LG) are as defined herein.

DETAILED DESCRIPTION

Before the present methods and systems are disclosed and described, itis to be understood that the methods and systems are not limited tospecific synthetic methods, specific components, or to particularcompositions. It is also to be understood that the terminology usedherein is for the purpose of describing particular embodiments only andis not intended to be limiting.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Ranges may be expressed herein as from “about” oneparticular value, and/or to “about” another particular value. When sucha range is expressed, another embodiment includes from the oneparticular value and/or to the other particular value. Similarly, whenvalues are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. It will be further understood that the endpoints of each ofthe ranges are significant both in relation to the other endpoint, andindependently of the other endpoint.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances where itdoes not.

Throughout the description and claims of this specification, the word“comprise” and variations of the word, such as “comprising” and“comprises,” means “including but not limited to,” and is not intendedto exclude, for example, other additives, components, integers or steps.“Exemplary” means “an example of” and is not intended to convey anindication of a preferred or ideal embodiment. “Such as” is not used ina restrictive sense, but for explanatory purposes.

Disclosed are components that can be used to perform the disclosedmethods and systems. These and other components are disclosed herein,and it is understood that when combinations, subsets, interactions,groups, etc. of these components are disclosed that while specificreference of each various individual and collective combinations andpermutation of these may not be explicitly disclosed, each isspecifically contemplated and described herein, for all methods andsystems. This applies to all aspects of this application including, butnot limited to, steps in disclosed methods. Thus, if there are a varietyof additional steps that can be performed it is understood that each ofthese additional steps can be performed with any specific embodiment orcombination of embodiments of the disclosed methods.

Pharmaceutically acceptable salts are salts that retain the desiredbiological activity of the parent compound and do not impart undesirabletoxicological effects. Examples of such salts are acid addition saltsformed with inorganic acids, for example, hydrochloric, hydrobromic,sulfuric, phosphoric, and nitric acids and the like; salts formed withorganic acids such as acetic, oxalic, tartaric, succinic, maleic,fumaric, gluconic, citric, malic, methanesulfonic, p-toluenesulfonic,napthalenesulfonic, and polygalacturonic acids, and the like; saltsformed from elemental anions such as chloride, bromide, and iodide;salts formed from metal hydroxides, for example, sodium hydroxide,potassium hydroxide, calcium hydroxide, lithium hydroxide, and magnesiumhydroxide; salts formed from metal carbonates, for example, sodiumcarbonate, potassium carbonate, calcium carbonate, and magnesiumcarbonate; salts formed from metal bicarbonates, for example, sodiumbicarbonate and potassium bicarbonate; salts formed from metal sulfates,for example, sodium sulfate and potassium sulfate; and salts formed frommetal nitrates, for example, sodium nitrate and potassium nitrate.Pharmaceutically acceptable and non-pharmaceutically acceptable saltsmay be prepared using procedures well known in the art, for example, byreacting a sufficiently basic compound such as an amine with a suitableacid comprising a physiologically acceptable anion. Alkali metal (forexample, sodium, potassium, or lithium) or alkaline earth metal (forexample, calcium) salts of carboxylic acids can also be made.

The term “alkyl” as used herein is a branched or unbranched hydrocarbongroup such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and thelike. The alkyl group can also be substituted or unsubstituted. Unlessstated otherwise, the term “alkyl” contemplates both substituted andunsubstituted alkyl groups. The alkyl group can be substituted with oneor more groups including, but not limited to, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol. An alkyl group which contains no double or triplecarbon-carbon bonds is designated a saturated alkyl group, whereas analkyl group having one or more such bonds is designated an unsaturatedalkyl group. Unsaturated alkyl groups having a double bond can bedesignated alkenyl groups, and unsaturated alkyl groups having a triplebond can be designated alkynyl groups. Unless specified to the contrary,the term alkyl embraces both saturated and unsaturated groups.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, etc. The term “heterocycloalkyl” is a cycloalkyl group asdefined above where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, selenium or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Unlessstated otherwise, the terms “cycloalkyl” and “heterocycloalkyl”contemplate both substituted and unsubstituted cyloalkyl andheterocycloalkyl groups. The cycloalkyl group and heterocycloalkyl groupcan be substituted with one or more groups including, but not limitedto, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol. A cycloalkyl groupwhich contains no double or triple carbon-carbon bonds is designated asaturated cycloalkyl group, whereas an cycloalkyl group having one ormore such bonds (yet is still not aromatic) is designated an unsaturatedcycloalkyl group. Unless specified to the contrary, the term cycloalkylembraces both saturated and unsaturated, non-aromatic, ring systems.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer, diastereomer, and meso compound,and a mixture of isomers, such as a racemic or scalemic mixture. Acompound depicted with wedges and dashed lines for bonds contemplatesboth the specifically depicted stereoisomer, as well the racemicmixture. The term “enantioenriched” means that the depicted enantiomeris present in a greater amount than the non-depicted enantiomer.

The term “aryl” as used herein is an aromatic ring composed of carbonatoms. Examples of aryl groups include, but are not limited to, phenyland naphthyl, etc. The term “heteroaryl” is an aryl group as definedabove where at least one of the carbon atoms of the ring is replacedwith a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur,selenium or phosphorus. The aryl group and heteroaryl group can besubstituted or unsubstituted. Unless stated otherwise, the terms “aryl”and “heteroaryl” contemplate both substituted and unsubstituted aryl andheteroaryl groups. The aryl group and heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl,heteroaryl, aldehyde, amino, carboxylic acid, ester, ether, halide,hydroxy, ketone, nitro, silyl, sulfo-oxo, or thiol.

Exemplary heteroaryl and heterocyclyl rings include: benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aHcarbazolyl, carbolinyl, chromanyl, chromenyL cirrnolinyl,decahydroquinolinyl, 2H,6H˜1,5,2-dithiazinyl, dihydrofuro[2,3b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl,imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, and xanthenyl.

The terms “alkoxy,” “cycloalkoxy,” “heterocycloalkoxy,” “cycloalkoxy,”“aryloxy,” and “heteroaryloxy” have the aforementioned meanings foralkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, furtherproviding said group is connected via an oxygen atom.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valencies of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. Unless specifically stated, a substituent that is saidto be “substituted” is meant that the substituent can be substitutedwith one or more of the following: alkyl, alkoxy, alkenyl, alkynyl,cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aldehyde, amino,carboxylic acid, ester, ether, halide, hydroxy, ketone, nitro, silyl,sulfo-oxo, or thiol.

Disclosed herein are methods of preparing oseltamivir by stereoselectivedirect diazidation of a compound of Formula (I):

wherein R¹ is selected from R^(1a), C(O)R^(1a), C(O)OR^(1a),C(O)N(R^(1a))₂, Si(R^(1a))₃, wherein R^(1a) is in each caseindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, andC₁₋₈heteroaryl;

wherein R^(h) is hydrogen and R² can be a leaving group like F, Cl, Br,I, NO₂, CN, OTs, or OMs;

R³ can be hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl,

which includes the step of contacting the compound of Formula (I) withan iron compound, an azide source, an activator, and a ligand, to give acompound of Formula (II):

wherein R¹, R², R³ and R^(h) have the meanings given above, or R^(h) andR² together form a double bond.

Suitable iron compounds include iron (II) salts such as Fe(OTf)₂,Fe(NTf₂)₂, Fe(BF₄)₂, FeF₂, FeCl₂, Fe(OAc)₂, FeI₂, FeBr₂, Fe(ClO₄)₂,FeSO₄, iron (II) oxalate, as well as iron (III) salts like FeCl₃, FeBr₃,FeF₃, Fe₂(SO₄)₃, Fe(NO₃)₃, FePO₄, iron (III) oxalate, iron citrate, andcombinations thereof. The iron compound is generally included in asubstoichiometric amount relative to the compound of Formula (I). Forinstance, the iron compound can be included in an amount from 0.1-20 mol%, from 0.5-10 mol %, from 1-10 mol %, from 1-7.5 mol %, from 2.5-7.5mol %, or from 4-6 mol %.

Azide sources include compounds like R₃Si—N₃, in which R isindependently selected from C₁₋₈alkyl or aryl. Preferred azide sourcesinclude TMS-N₃, TES-N₃, and TBDMS-N₃. In certain embodiments, at least atwo-fold excess of azide source, relative to the compound of Formula (I)can be used, and it is preferable that at least 2.5 equivalents, atleast 3 equivalents, at least 3.5 equivalents, at least 4 equivalents,at least 5 equivalents, at least 7.5 equivalents, or at least 10equivalents of the azide source is employed relative the compound ofFormula (I). In some embodiments, from 2-8 equivalents, from 2-6equivalents, from 2-4 equivalents, or from 4-6 equivalents of the azidesource is used.

The activator can be a hypervalent iodine compound or a peroxy compound.In some cases, the hypervalent iodine is an iodine (III) compound, ofwhich iodobenzene dichloride, bisactetoxyiodo benzene (PIDA or BAIB),and benziodoxole are exemplary species. Suitable peroxo compoundsincluding peroxyacids, especially perbenzoic acids like2-chloroperoxybenzoic acid, 2-iodoperoxybenzoic acid, as well asperoxyacetic acid (which may also be designated peracetic acid),trifluoroperacetic acid, chloroperacetic acid, and esters thereof.Preferred esters include C₁₋₈ esters, e.g., methyl, ethyl, propyl, butyland the like. A preferred ester is tert-butyl, e.g.,tert-butyl-peroxoacetate, tert-butyl-2-iodobenzoperoxoate ortert-butyl-2-chlorobenzoperoxoate.

Suitable ligands include bidentate and polydentate ligands. As usedherein, a bidentate ligand bears two Lewis basic atoms (nitrogen,oxygen, sulfur, phosphorous, etc. . . . ) which are capable ofinteraction with the same Lewis acid. Likewise, a tridentate ligandbears three Lewis basic atoms capable of interaction with the same Lewisacid. Suitable ligands include substituted heterocyclic and heteroarylrings, including bispyridines, bisoxazole, and pyridine bisoxazoles.

In some cases, the ligand can have the formula:

wherein m is selected from 0, 1, 2, or 3, and in each case R^(LA),R^(LB), R^(LC), and R^(LD) are independently selected from R, OR, N(R)₂,PR₃, SiR₃, SR, SO₂R, SO₂N(R)₂, C(O)R; C(O)OR, OCOR; C(O)N(R)₂,OC(O)N(R)₂, N(R)C(O)N(R)₂, F, Cl, Br, I, cyano, and nitro, wherein R isin each case independently selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, orC₁₋₈heterocyclyl; and any two or more of R^(LA), R^(LB), R^(LC), R^(LD),and R may together form a ring.

In certain preferred embodiments, the ligand can the formula:

wherein m is selected from 0, 1, 2, or 3, and each of R^(7a), R^(7b),R^(8a), and R^(8b) are independently selected from R, OR, N(R)₂, PR₃,SiR₃, SR, SO₂R, SO₂N(R)₂, C(O)R C(O)OR, OCOR; C(O)N(R)₂, OC(O)N(R)₂,N(R)C(O)N(R)₂, F, Cl, Br, I, cyano, and nitro, wherein R is in each caseindependently selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, or C₁₋₈heterocyclyl;and any two or more of R^(7a), R^(7b), R^(8a), R^(8b), R^(LD), and R maytogether form a ring.

In some embodiments, the ligand can be one of the following bidentate ortridentate compounds:

The skilled person will appreciate certain ligands can exist inenantioenriched form. Unless specified explicitly to the contrary, theligands depicted above can be used either as the racemic mixture of inenantioenriched form. The ligand is generally included in the reactionmixture in a stoichiometric equivalent amount to the iron compound,i.e., the stoichiometric ratio of the ligand to iron compound isapproximately 1:1.

The diazidation reaction can be carried out in a suitable solvent, forinstance a polar, aprotic solvent. Exemplary solvents include acetone,ethyl acetate, methylene chloride, acetonitrile, diethyl ether,1,2-dichloroethane, dimethylformamide, dimethylsulfoxide,1,2-dimethoxyethane, diethylene glycol dimethyl ether, nitromethane,methyl-t-butyl ether, N-methyl-2-pyrrolidinone, tetrahydrofuran, andcombinations thereof. In some embodiments, a relatively non-polarsolvent can also be added, for instance, hexane, toluene, or petroleumethers. In some instances, a small amount of an alcohol may be includedas well. For instance, methanol, ethanol, n-propanol, isopropanol,n-butanol, tert-butanol, or ethylene glycol may be added, generally in asub-stoichiometric amount relative to the compound of Formula (I), e.g.,less than 1 equivalent, less than 0.75 equivalents, less than 0.5equivalents, or less than 0.25 equivalents. In some embodiments, from0.1-1, from 0.1-0.75, from 0.1-0.5, or from 0.1-0.25 equivalents of thealcohol, relative to the compound of Formula (I) can be added.

In some embodiments, R¹ is hydrogen or C(O)R^(1a), and it is preferablethat R^(1a) is C₁₋₈alkyl, e.g. methyl, ethyl or 2-propyl. NO₂ is apreferred R² group, and ethyl, as it occurs in oseltamivir, is thepreferred R³ group. The diazidation reaction can provide the compound ofFormula (II) in the desired (and depicted) stereochemical configurationin an amount that is at least 85%, at least 90%, at least 92.5%, atleast 95%, at least 97.5%, or at least 99%, relative to the total amountof the reaction product.

In some embodiments, the diazidation reaction can be conducted using thecompound of Formula (I) in racemic form. In such embodiments, the ligandmay be achiral or racemic, and the resulting racemic mixture of thecompound of Formula (II) may be converted to enantioenriched form usingconventional methods. In other embodiments, the compound of Formula (I)is in racemic form, and the ligand is enantioenriched. In such cases,when only a single equivalent of azide source is used (relative to theolefin in Formula (I), only the desired enantiomer will be undergodiazidation, and the enantioenriched diazide can be separated from theunreacted, opposite enantiomer. In some embodiments, the diazidationreaction can be conducted using the compound of Formula (I) inenantioenriched form. Preferably, the enantiomeric excess of theenantioenriched compound of Formula (I) is at least 85%, at least 90%,at least 92.5%, at least 95%, at least 97.5%, or at least 99%. In suchembodiments, the ligand may be achiral or racemic. In other cases, theligand may be enantioenriched itself, and the matching of the ligand andsubstrate will further enhance the enantiomeric excess of the product.In certain embodiments, the ligand is provided in racemic form, and thecompound of Formula (I) is provided in enantioenriched form, as definedabove.

In some embodiments, the compound of Formula (II) may be converted tothe compound of Formula (III):

by elimination of H—R². R³ has the same meanings given above, and R^(1′)can be R^(1a′), C(O)R^(1a′), C(O)OR^(1a′), C(O)N(R^(1a′))₂,Si(R^(1a′))₃, wherein R^(1a′) is in each case independently selectedfrom the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl. Thisprocess may be carried taking advantage of the acidity of the R^(h)proton, using either acid or base mediated chemistries. In someinstances, an R¹ protecting group will be removed under these conditionsas well, leading to compounds in which R^(1′) is hydrogen. In suchinstances, the alkoxy group found in oseltamivir may be directlyinstalled, e.g., R^(1′) is 3-pentyl. Such compounds may be prepared byreaction with a compound of formula X—CH(CH₂CH₃)₂, in which X is Cl, Br,I, OMs, OTs, or OC(NH)CCl₃.

The compound of Formula (III) can be converted to the compound ofFormula (IV):

by reduction of the azide groups, in which R⁴, R^(4′), R⁵, and R^(5′)are independently selected from R^(z), C(O)R^(z), C(O)OR^(z),C(O)N(R^(z))₂, Si(R^(z))₃, wherein R^(z) is in each case independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heteroaryl.Preferred reductive condition include the use of an trialkyl and triarylphosphines like Ph₃P, in a mixed aqueous/organic solvent.Solid-supported alkyl- and arylphosphines can also be used. In someembodiments, catalytic hydrogenation can be employed, for instance usingruthenium, rhodium, iridium, palladium, platinum, or nickel catalysts.Preferred R^(1′) groups for the reduction reaction include hydrogen,C(═O)CH₃, and 3-pentyl.

The vicinal di-primary amine compound (i.e., R⁴, R^(4′), R⁵, and R^(5′)are each hydrogen) may be selectively protected at the 5 position togive a compound in which R⁴, R^(4′), and R^(5′) are each hydrogen, andR⁵ is C(O)OR^(z) or Si(R^(z))₃, followed by acylation at the 4-position,e.g, R^(4′) is hydrogen and R⁴ is C(O)CH₃, and finally conversion of R⁵to hydrogen. This process can be advantageously carried out when R^(1′)is 3-pentyl. At any stage of this process, the compound of Formula (IV)may be reacted with a chiral acid and selectively crystallized toincrease the enantiomeric excess of the compound. Suitable chiral acidsinclude tartaric acid (and diester derivative thereof like dibenzoyltartaric acid, camphorsulfonic acid, bromo-camphorsulfonic acid, andmandelic acid.

In some embodiments, the compound of Formula (I) may be converted to acompound of Formula (IV-a):

in which R^(1′), R³, R⁴, R^(4′), R⁵, and R^(5′) are as defined above,R^(h) is a hydrogen atom, and R² is selected from F, Cl, Br, I, NO₂, CN,OTs, and OMs. R⁴, R^(4′), R⁵, and R^(5′) can be converted to the groupsfound in oseltamivir as described above for the compound of Formula(IV), and the elimination of H—R² may be conducted at any advantageouspoint in the route.

The compound of Formula (IV) or (IV-a), when R^(4′), R⁵, and R^(5′) areeach hydrogen and R⁴ is C(O)CH₃ may be converted to the phosphate saltto give the active ingredient found in Tamiflu. In instances in whichR^(5′) is protected with an acid labile group during the installation ofR⁴, the compound may be deprotected with phosphoric acid to give theactive ingredient found in Tamiflu.

The compound of Formula (I) may be obtained from a cycloadditionreaction between compound of formula (VI):

and a compound of formula (VII):

to give the compound of formula (I), wherein R¹, R², R³ and R^(h) are asdefined above. Preferred R¹ moieties include acyl such as acetyl,benzoyl, and then like. The compound of Formula (VI) can easily beprepared from crotonaldehyde using conventional conditions.

The compound of Formula (VII) may prepared in situ from a compound ofFormula (VIII):

wherein R^(LG) represents a leaving group like Cl, Br, I, OTs, or OMs,and R² is sufficient to increase the acidity of the depicted hydrogenatom. In such cases, it is preferred that R² is nitro. In suchembodiments, the compound of Formula (VIII) may be combined with thecompound of Formula (VI) in the presence of a mild base.

The cycloaddition reaction may be conducted in the presence of a chiralcatalyst or auxiliary to afford the compound of Formula (I) inenantioenriched form. In other embodiments, the compound of Formula (I)may be produced as the racemic mixture, and then enantioenriched. Apreferred method of enantioenriching the compound of Formula (I) when R¹is acyl is an enzymatic kinetic resolution:

wherein R², R³, R^(h) are as defined above, and R^(e) is an alkyl oraryl group. In some embodiments, the compound of Formula (I) will havethe following relative configuration:

The enzymatic resolution may be conducted using a suitable lipase in anaqueous alcoholic solvent. Suitable lipases include lipase from porcinepancreas, lipase from Rhizopus oryzae, lipase from wheat germ, lipasefrom human pancreas, lipase from Candida rugosa, lipase from Aspergillusniger, lipase from Thermomyces lanuginosus, lipase from Rhizomucormiehei, lipase from Pseudomonas cepacian, lipase from Aspergillusoryzae, lipase from Pseudomonas sp., lipase from Pseudomonasfluorescens, lipase from Rhizopus niveus, lipase from Mucor miehei,lipase from Mucor javanicus, lipase from Burkholderia sp., lipase fromCandida Antarctica, lipase from Candida lipolytica, Amano lipase PS,from Burkholderia cepacian, lipase B Candida antarctica, recombinantfrom Aspergillus oryzae, lipase, Chromobacterium viscosum, lipase ACandida antarctica, recombinant from Aspergillus oryzae, lipase fromCandida antarctica, CLEA, lipase from Candida rugosa, CLEA, lipase fromThermomyces lanuginosa, CLEA, lipase produced by Aspergillus oryzae,pancreatin lipase, Amano lipase PS, Amano lipase A from Aspergillusniger, Amano Lipase from Pseudomonas fluorescens, lipoprotein lipasefrom Burkholderia sp., lipoprotein lipase from bovine milk, Amano lipaseM from Mucor javanicus, lipoprotein lipase from Pseudomonas sp., Amanolipase G from Penicillium camemberti. Amano lipases, for instance AmanoLipase from Pseudomonas fluorescens, are especially preferred for theenzymatic step. The enantiomeric excess of the unreacted isomer can beat least 85%, at least 90%, at least 92.5%, at least 95%, at least97.5%, or at least 99%. Likewise, the enantiomeric excess of thedeacylated isomer can be at least 85%, at least 90%, at least 92.5%, atleast 95%, at least 97.5%, or at least 99%.

The unreacted enantiomer may be separated from the hydrolyzed productusing conventional techniques. If desired, the stereochemistry of thehydroxy group-bearing carbon on the undesired enantiomer can be invertedusing Mitsunobu and related chemistries.

EXAMPLES

The following examples are for the purpose of illustration of theinvention only and are not intended to limit the scope of the presentinvention in any manner whatsoever.

Example 1: Synthesis of Cyclohexene Substrate

To an oven-dried 500 mL round bottom flask equipped with a stir bar wasadded finely ground NaOAc.3H₂O (43.1 g, 316.8 mmol, 2.0 equiv). Theflask was evacuated and backfilled with N₂. Subsequently, anhydrousCH₂Cl₂ (320 mL), (E)-buta-1,3-dien-1-yl acetate 1 (35.5 g, 316.8 mmol,2.0 equiv) and ethyl 2-bromo-3-nitropropanoate 2 (35.8 g, 158.4 mmol,1.0 equiv) were added. The reaction mixture was stirred at roomtemperature for 48 h until 2 was fully consumed (monitored by TLC). Thereaction mixture was filtered and the solid was washed with CH₂Cl₂ (100mL). The combined CH₂Cl₂ filtrate was washed with brine (100 mL) anddried over Na₂SO₄. After concentration in vacuo, the crude product wasrecrystallized from ethanol (100 mL) to furnish the desired product(±)-3 (29.3 g, 72%, dr>20:1, m.p. 75-76° C.).

(±)-Ethyl-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate ((±)-3)

IR ν_(max) (neat)/cm⁻¹: 2979 (w), 1737 (s), 1559 (s), 1373 (m), 1226(s), 1186 (s), 1027 (m), 924 (w); ¹H NMR (400 MHz, CDCl₃) δ 6.10-5.90(m, 2H), 5.84-5.68 (m, 1H), 4.93 (dd, J=12.1, 4.2 Hz, 1H), 4.32-4.12 (m,2H), 3.45 (td, J=11.8, 6.2 Hz, 1H), 2.74 (ddd, J=22.3, 11.2, 7.7 Hz,1H), 2.33-2.19 (m, 1H), 1.99 (s, 3H), 1.28 (t, J=7.1 Hz, 3H); ¹³C NMR(100 MHz, CDCl₃) δ 172.4, 169.4, 131.2, 122.6, 83.3, 65.8, 61.6, 38.0,28.9, 20.6, 14.1; LRMS (ESI, m/z): calcd for C₁₁H₁₅NNaO₆ ⁺, [M+Na⁺],280.1, found 280.1.

To a 100 mL round bottom flask were added Amano Lipase from Pseudomonasfluorescens (1.0 g, 50 wt %),(±)-ethyl-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate (±)-3 (2.0 g,7.78 mmol, 1.0 equiv), aqueous citric acid—Na₂HPO₄ buffer (44.2 mL,pH=6.0, c=0.037 M) and ethanol (4.4 mL). The mixture was stirred at roomtemperature for 26 h. EtOAc (30 mL) was added to dilute the reaction.The organic phase was separated from the aqueous phase and the aqueousphase was further extracted with EtOAc (30 mL×4). The combined organicphase was washed with brine (50 mL) and dried over Na₂SO₄. Afterconcentration in vacuo, the residue was purified through columnchromatography (hexanes/EtOAc: from 50:1 to 2:1) to afford thehydrolyzed product (−)-4 as colorless oil (805 mg, 48% yield, 99% ee)along with the enantio-enriched starting material (+)-3 (800 mg, 40%yield, 98% ee).

(−)-Ethyl (1R,5R,6S)-5-hydroxy-6-nitrocyclohex-3-ene-1-carboxylate((−)-4)

[α]_(D) ²⁰=−294.5° (c 1.025, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 3442 (br),2983 (w), 2930 (w), 1726 (s), 1551 (s), 1379 (m), 961 (s); ¹H NMR (400MHz, CDCl₃) δ 6.07-5.89 (m, 2H), 4.87 (dd, J=11.6, 4.0 Hz, 1H),4.83-4.82 (m, 1H), 4.37-4.07 (m, 2H), 3.42 (td, J=11.5, 6.0 Hz, 1H),2.72 (ddd, J=18.4, 6.0, 3.9 Hz, 1H), 2.30-2.20 (m, 1H), 2.11 (d, J=6.6Hz, 1H), 1.30 (t, J=7.1 Hz, 1H); ¹³C NMR (100 MHz, CDCl₃) δ 172.9,129.5, 125.6, 86.1, 64.4, 61.5, 37.4, 29.0, 14.0; LRMS (ESI, m/z): calcdfor C₉H₁₃NNaO₅ ⁺, [M+Na⁺], 238.1, found 238.1.

(+)-Ethyl (1S,5S,6R)-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate((+)-3)

[α]_(D) ²⁰=+363.1° (c 1.175, CHCl₃). IR, NMR and LRMS are the same as(±)-3.

Note: the enantiomeric (−)-3 can be readily recovered from (−)-4.

To a flame-dried 50 mL round bottom flask were added ethyl(1R,5R,6S)-5-hydroxy-6-nitrocyclohex-3-ene-1-carboxylate (−)-4 (860 mg,4.0 mmol, 1.0 equiv) and DMAP (49 mg, 0.4 mmol, 0.1 equiv). After theflask was evacuated and backfilled with N₂ twice, anhydrous CH₂Cl₂ (5.0mL) was added via a syringe and the mixture was cooled down to 0° C.Subsequently, acetyl chloride (0.34 mL, 4.8 mmol, 1.2 equiv) was addedto the flask followed by pyridine (0.39 mL, 4.8 mmol, 1.2 equiv). Thereaction mixture was stirred at 0° C. for 2 h until (−)-4 was fullyconsumed (monitored by TLC). Saturated aqueous NH₄Cl solution (5 mL) wasadded to quench the reaction. The organic phase was separated fromaqueous phase and the aqueous phase was further extracted with CH₂Cl₂(20 mL×3). The combined organic phase was washed with brine (30 mL) anddried over Na₂SO₄. After concentration in vacuo, the residue waspurified through column chromatography (hexanes/EtOAc: from 50:1 to 4:1)to afford the desired product (−)-3 as a white solid (875 mg, 85%yield).

Ethyl (1R,5R,6S)-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate ((−)-3)

[α]_(D) ²⁰=−360.20 (c 1.251, CHCl₃). IR, NMR and LRMS are the same as(±)-3.

To a 100 mL round bottom flask were addedethyl-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate (+)-3 (2.0 g, 7.78mmol, 1.0 equiv), EtOH (39 mL) and H₂SO₄ (39 mL, 3.0 M, 116.7 mmol, 15.0equiv). The mixture was stirred at 35° C. for 12 h. EtOAc (50 mL) wasadded to dilute the reaction. The organic phase was separated from theaqueous phase and the aqueous phase was further extracted with EtOAc (30mL×3). The combined organic phase was washed with brine (80 mL) anddried over Na₂SO₄. After concentration in vacuo, the residue waspurified through column chromatography (hexanes/EtOAc: from 50:1 to 2:1)to afford the hydrolyzed product (+)-4 as colorless oil (1.56 g, 93%yield).

(+)-Ethyl (1R,5R,6S)-5-hydroxy-6-nitrocyclohex-3-ene-1-carboxylate((+)-4)

[α]_(D) ²⁰=+294.5° (c 1.025, CHCl₃). IR, NMR and LRMS are the same as(−)-4.

Example 2: Stereoselective Diazidation

To a flame-dried 250 mL round bottom flask equipped with a stir bar wereadded Fe(OAc)₂ (169 mg, 0.97 mmol, 5 mol %), achiral ligand L1 (265 mg,0.97 mmol, 5 mol %), ethyl(1S,5S,6R)-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate (+)-3 (5.0 g,19.44 mmol, 1.0 equiv) and benziodoxole (10.3 g, 38.9 mmol, 2.0 equiv).After the flask was evacuated and backfilled with N₂ three times,anhydrous CH₂Cl₂ (20 mL) and MeCN (2.0 mL) were added via syringes andthe mixture was stirred at room temperature for 10 min. Subsequently,freshly opened TMSN₃ (12.8 mL, 97.2 mmol, 5.0 equiv) was added to theflask at room temperature within 8 h using a syringe pump. The reactionmixture was stirred for additional 2 h until (+)-3 was fully consumed(monitored by TLC). Et₂O (150 mL) was added to dilute the reaction andthe resulting suspension was stirred for 10 min. The mixture wasfiltered and the solid was washed with Et₂O (20 mL×2). The combinedfiltrate was washed with saturated NaHCO₃ solution (160 mL), brine (100mL) and dried over Na₂SO₄. The mixture was filtered through a silica gelpad (ca. 6 cm long×6 cm diameter) and the pad was washed with ether (100mL×3). After concentration in vacuo, the crude diazidation product 5 wasobtained as a yellow solid, which was used in the next step directlywithout further purification. The crude yield and dr value were obtainedby quantitative ¹H NMR experiment using an internal standard (85% NMRyield, dr: 7.4:1). For characterization purposes, it was purifiedthrough column chromatography (hexanes/EtOAc: from 20:1 to 6:1) toafford the desired pure product 5a as a white solid (4.78 g, 72% yield).

Ethyl(1S,2R,3S,4R,5S)-3-acetoxy-4,5-diazido-2-nitrocyclohexane-1-carboxylate(5a)

[α]_(D) ²⁰=−6.4° (c 1.13, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 2966 (w), 2098(s), 1748 (s), 1727 (s), 1557 (s), 1383 (m), 1232 (s), 1189 (s), 1042(m), 1024 (m); ¹H NMR (400 MHz, CDCl₃) δ 5.34 (dd, J=6.8, 4.3 Hz, 1H),5.23 (dd, J=6.7, 4.3 Hz, 1H), 4.32-4.16 (m, 3H), 3.68 (q, J=6.1 Hz, 1H),3.46 (q, J=6.4 Hz, 1H), 2.21 (t, J=6.1 Hz, 2H), 2.12 (s, 3H), 1.31 (t,J=7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.2, 169.4, 81.7, 69.6,62.4, 60.9, 57.8, 34.0, 27.4, 20.6, 14.1; LRMS (ESI, m/z): calcd forC₁₁H₁₅N₇NaO₆ ⁺, [M+Na⁺], 364.1, found 364.1.

To an oven-dried 250 mL round bottom flask were added the crudediazidation product ethyl(1S,2R,3S,4R,5S)-3-acetoxy-4,5-diazido-2-nitrocyclohexane-1-carboxylate5a obtained in last step (14.6 mmol, 1.0 equiv). After the flask wasevacuated and backfilled with N₂ twice, EtOH (24 mL) and methanesulfonicacid (2.84 mL, 43.7 mmol, 3.0 equiv) were added via syringes. Themixture was warmed up to 55° C. and stirred at this temperature for 7 huntil the starting material was fully consumed (monitored by TLC). Thereaction mixture was moved to ice-bath and diluted with EtOH (122 mL).Subsequently, LiOH.H₂O (2.76 g, 65.7 mmol, 4.5 equiv) was addedportion-wise and the mixture was stirred at 0° C. for additional 30 minuntil the intermediate was consumed (monitored by NMR). AcOH (0.83 mL,1.5 equiv) was added to quench the reaction. EtOH was removed in vacuo,and the residue was diluted with EtOAc (50 mL) and water. The organicphase was separated from aqueous phase and the aqueous phase was furtherextracted with EtOAc (50 mL×2). The combined organic phase was driedover Na₂SO₄. After concentration in vacuo, the residue was purifiedthrough column chromatography (hexanes/EtOAc: from 30:1 to 3:1) toafford the desired product 6 as yellow oil (2.98 g, 61% yield over threesteps).

Ethyl (3R,4R,5S)-4,5-diazido-3-hydroxycyclohex-1-ene-1-carboxylate (6)

[α]_(D) ²⁰=−102° (c 0.75, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 3435 (br),2981 (w), 2103 (s), 1704 (m), 1656 (w), 1250 (s), 1089 (m), 1043 (m),981 (w); ¹H NMR (400 MHz, CDCl₃) δ 6.79 (s, 1H), 4.33-4.28 (m, 1H), 4.25(q, J=7.1 Hz, 2H), 3.63 (td, J=10.2, 5.9 Hz, 1H), 3.52-3.40 (m, 1H),2.95 (dd, J=18.1, 5.8 Hz, 1H), 2.59-2.57 (m, 1H), 2.44-2.29 (m, 1H),1.33 (t, J=7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 165.5, 137.8, 128.5,70.8, 68.2, 61.4, 59.6, 30.1, 14.1; LRMS (ESI, m/z): calcd forC₉H₁₂N₆NaO₃ ⁺, [M+Na⁺], 275.1, found 275.1.

To a flame-dried sealable 2-dram vial (vial A) equipped with a stir barwere added Fe(NTf₂)₂ (62 mg, 0.1 mmol, 10 mol %) and the ligand L2 (24mg, 0.1 mmol, 10 mol %). After this vial was evacuated and backfilledwith N₂ twice, anhydrous CH₂Cl₂ (0.6 mL) and MeCN (0.2 mL) were addedvia syringes and the mixture was stirred at room temperature for 10 min.To a second flame-dried sealable 2-dram vial (vial B) equipped with astir bar was added ethyl(1S,5S,6R)-5-acetoxy-6-nitrocyclohex-3-ene-1-carboxylate (+)-3 (257 mg,1.0 mmol, 1.0 equiv) and tert-butyl 2-iodobenzoperoxoate 11 (800 mg, 2.5mmol, 2.5 equiv). After this vial was evacuated and backfilled with N₂twice, the catalyst solution in vial A, isopropanol (15 μL, 0.2 mmol,0.2 equiv) and freshly distilled TMSN₃ (133 μL, 1.0 mmol, 1.0 equiv)were added to vial B at 0° C. Subsequently, additional TMSN₃ (332 μL,2.5 mmol, 2.5 equiv) was added to vial B at 0° C. using a syringe pumpwithin 4 h. The reaction mixture was warmed up to 22° C. and keptstirring for 11 h. CH₂Cl₂ (4 mL) and saturated NaHCO₃ solution (0.5 mL)were added to quench the reaction and to remove any residual hydrazoicacid. The organic phase was separated from the aqueous phase, and it waswashed with saturated Na₂CO₃ solution (2 mL), brine (2 mL), and driedover Na₂SO₄. After concentration in vacuo, the dr was obtained byquantitative ¹H NMR experiment using an internal standard (86% NMRyield, dr: 4.8:1). The crude product was purified through columnchromatography (hexanes/EtOAc: from 20:1 to 6:1) to afford the desiredpure product 5a as a white solid (243 mg, 71% yield).

To a flame-dried 100 mL round bottom flask equipped with a stir bar wereadded Fe(OAc)₂ (61 mg, 0.35 mmol, 5 mol %), achiral ligand L1 (95 mg,0.35 mmol, 5 mol %), ethyl(1S,5S,6R)-5-hydroxy-6-nitrocyclohex-3-ene-1-carboxylate (+)-4 (1.5 g,6.97 mmol, 1.0 equiv) and benziodoxole (3.68 g, 13.94 mmol, 2.0 equiv).After the flask was evacuated and backfilled with N₂ three times,anhydrous CH₂Cl₂ (8 mL) and MeCN (0.8 mL) were added via syringes andthe mixture was stirred at room temperature for 10 min. Subsequently,freshly opened TMSN₃ (4.58 mL, 34.85 mmol, 5.0 equiv) was added to theflask at room temperature within 8 h using a syringe pump. The reactionmixture was stirred for additional 2 h until (+)-4 was fully consumed(monitored by TLC). Et₂O (50 mL) was added to dilute the reaction andthe resulting suspension was stirred for 10 min. The mixture wasfiltered and the solid was washed with Et₂O (20 mL×2). The combinedfiltrate was first washed with aq. H₂SO₄ (1 M) and then saturated NaHCO₃solution (100 mL), brine (50 mL) and dried over Na₂SO₄. Afterconcentration in vacuo, the residue was purified through columnchromatography (hexanes/EtOAc: from 50:1 to 2:1) to afford the desiredproduct 5c as colorless oil (1.58 g, 76% yield).

Ethyl(1S,2R,3S,4R,5S)-4,5-diazido-3-hydroxy-2-nitrocyclohexane-1-carboxylate(5c)

IR ν_(max) (neat)/cm⁻¹: 3462 (w), 2920 (w), 2110 (s), 1729 (s), 1558(s), 1377 (m), 1258 (s), 1200 (m), 1095 (m), 1021 (m), 955 (w), 874 (w);¹H NMR (400 MHz, CDCl₃) δ 5.04 (dd, J=8.4, 3.9 Hz, 1H), 4.40-4.36 (m,1H), 4.27-4.18 (m, 2H), 4.06 (t, J=5.4 Hz, 1H), 3.78 (dd, J=9.6, 5.2 Hz,1H), 3.48 (td, J=8.7, 5.2 Hz, 1H), 3.24 (d, J=7.0 Hz, 1H), 2.26-2.07 (m,2H), 1.29 (t, J=7.1 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃) δ 170.9, 83.7,70.0, 62.7, 62.2, 58.3, 37.4, 27.4, 14.0; LRMS (ESI, m/z): calcd forC₉H₁₃N₇O₅Na⁺, [M+Na⁺], 322.1, found 322.1.

To a 100 mL round bottom flask were added the diazidation product 5c(1.46 g, 4.88 mmol, 1.0 equiv) and EtOH (49 mL). After the flask wasmoved to ice-bath, LiOH.H₂O (0.61 g, 14.64 mmol, 3.0 equiv) was addedportion-wise and the mixture was stirred at 0° C. for 30 min until thestarting material was fully consumed (monitored by TLC). AcOH (0.56 mL,9.76 mmol, 2 equiv) was added to quench the reaction. EtOH was removedin vacuo, and the residue was diluted with EtOAc (30 mL) and water (20mL). The organic phase was separated from aqueous phase and the aqueousphase was further extracted with EtOAc (30 mL×2). The combined organicphase was dried over Na₂SO₄. After concentration in vacuo, the residuewas purified through column chromatography (hexanes/EtOAc: from 30:1 to3:1) to afford the desired product 6 as yellow oil (1.12 g, 91% yield).

Example 3: Synthesis of Oseltamivir

To a 100 mL round bottom flask with a stir bar was added ethyl(3R,4R,5S)-4,5-diazido-3-hydroxycyclohex-1-ene-1-carboxylate 6 (2.92 g,11.6 mmol, 1.0 equiv). After the flask was evacuated and backfilled withN₂ twice, THF (50 mL) and H₂O (2.1 mL, 115.9 mmol, 10 equiv) were addedvia syringes. Subsequently, Ph₃P (6.9 g, 26.7 mmol, 2.3 equiv) in THF(20 mL) was added drop-wise to the reaction at 0° C. The reactionmixture was warmed up to room temperature and stirred for 8 h (monitoredby IR until the absorption of azido groups disappeared). The reactionmixture will be used directly in the next step without workup andpurification.

The reaction mixture from last step was added drop-wise to another 250mL round bottom flask charged with a stir bar, TsOH.H₂O (5.5 g, 28.9mmol, 2.5 equiv), Et₂O (80 mL) and THF (10 mL). The reaction mixture wasstirred at room temperature for 1 h with the formation of whiteprecipitates. The reaction mixture was filtered. The precipitate wasdissolved in water (30 mL) and then washed with EtOAc (30 mL×2) toremove residue Ph₃PO. The filtrate was concentrated in vacuo andre-dissolved in EtOAc (10 mL). The organic phase was extracted withwater (30 mL) and the combined aqueous phase will be used directly inthe next step.

The aqueous solution from last step was cooled to 0° C. and NaHCO₃ (9.3g, 110.6 mmol, 10 equiv) was carefully added portion-wise. The resultingsolution was stirred at 0° C. for 5 min and methyl chloroformate (2.33mL, 30.1 mmol, 2.6 equiv) was added. The mixture was warmed up to roomtemperature and stirred for additional 2 h. EtOAc was added to thereaction mixture. The organic phase was separated from the aqueous phaseand the aqueous phase was further extracted with EtOAc (30 mL×3). Thecombined organic phase was dried over Na₂SO₄. After concentration invacuo, the residue was purified through column chromatography(hexanes/EtOAc: from 50:1 to 2:1) to afford the desired product 7 as awhite solid (2.93 g, 80% yield, m.p. 58-59° C.).

Ethyl(3R,4R,5S)-4,5-bis((ethoxycarbonyl)amino)-3-hydroxycyclohex-1-ene-1-carboxylate(7)

[α]_(D) ²⁰=−26.7° (c 0.325, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 3319 (m),2981 (w), 1692 (s), 1533 (s), 1447 (w), 1372 (w), 1239 (s), 1039 (s),986 (m), 861 (m); ¹H NMR (400 MHz, CDCl₃) δ 6.78 (s, 1H), 5.94 (d, J=8.6Hz, 1H), 5.72 (d, J=8.9 Hz, 1H), 4.31-4.30 (m, 1H), 4.27-4.22 (m, 1H),4.18 (q, J=7.1 Hz, 2H), 3.88-3.71 (m, 1H), 3.63 (s, 3H), 3.62 (s, 3H),2.82 (dd, J=17.5, 5.1 Hz, 1H), 2.34-2.18 (m, 1H), 1.26 (t, J=7.1 Hz,3H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 158.9, 157.7, 139.1, 128.7, 71.4,61.0, 58.8, 52.5, 52.4, 49.8, 31.3, 14.1; LRMS (ESI, m/z): calcd forC₁₃H₂₁N₂O₇ ⁺, [M+H⁺], 317.1, found 317.1.

To an oven-dried 50 mL round bottom flask equipped with a stir bar wereadded ethyl(3R,4R,5S)-4,5-bis((ethoxycarbonyl)amino)-3-hydroxycyclohex-1-ene-1-carboxylate7 (1.38 g, 4.4 mmol, 1.0 equiv) and 5 Å molecular sieves powder (1.5 g).After the flask was evacuated and backfilled with N₂ twice, anhydrousCH₂Cl₂ (9.0 mL) and freshly distilled pentan-3-yl2,2,2-trichloroacetimidate (17 mL, 95.8 mmol, 22 equiv) were added. Thereaction was cooled to 0° C. and TfOH (154 μL, 1.74 mmol, 0.4 equiv) wasadded. After the addition of TfOH, the reaction mixture was warmed up to28° C. and stirred at this temperature for 22 h until 7 was fullyconsumed (monitored by TLC). The mixture was cooled to 0° C., and Et₃N(0.6 mL, 4.4 mmol, 1.0 equiv) in CH₂Cl₂ (10 mL) was added to quench thereaction. The mixture was filtered and the solid was washed with CH₂Cl₂(10 mL×4). The filtrate was concentrated in vacuo and the residue waspurified through column chromatography (hexanes/EtOAc: from 30:1 to 2:1)to afford the desired product 8 as a white solid (1.21 g, 72% yield,m.p. 95-96° C.).

Ethyl(3R,4R,5S)-4,5-bis((methoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate(8)

[α]_(D) ²⁰=−54.6° (c 0.85, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 3313 (m),2921 (s), 1697 (s), 1544 (m), 1286 (m), 1231 (m), 1058 (m); ¹H NMR (400MHz, CDCl₃) δ 6.80 (s, 1H), 5.52 (s, 1H), 4.76 (s, 1H), 4.20 (q, J=6.7Hz, 2H), 4.06-3.74 (m, 3H), 3.67 (s, 3H), 3.65 (s, 3H), 3.39 (s, 1H),2.73 (d, J=17.1 Hz, 1H), 2.37 (d, J=11.5 Hz, 1H), 1.53-1.51 (m, 4H),1.37-1.21 (m, 3H), 0.89-0.88 (m, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 166.0,157.5, 157.1, 136.9, 129.3, 82.5, 77.3, 75.2, 60.9, 55.3, 52.3, 52.2,49.6, 30.4, 26.2, 25.8, 14.2, 9.4, 9.3; LRMS (ESI, m/z): calcd forC₁₈H₃₁N₂O₇ ⁺, [M+H⁺], 387.2, found 387.2.

To a flame-dried 50 mL round bottom flask equipped with a stir bar wereadded methyl(3R,4R,5S)-4,5-bis((methoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate8 (1.0 g, 2.6 mmol, 1.0 equiv) and anhydrous NaI (2.34 g, 15.6 mmol, 6.0equiv). After this flask was evacuated and backfilled with N₂ twice,anhydrous MeCN (5.2 mL) was added followed by drop-wise addition offreshly distilled TMSCl (1.98 mL, 15.6 mmol, 6.0 equiv) via a syringe.The mixture was warmed up to 40° C. and stirred at this temperature for12 h in dark. The reaction was cooled down to 0° C. and diluted withCH₂Cl₂ (30 mL). Saturated Na₂CO₃ solution (10 mL), H₂O (5 mL) andsaturated Na₂S₂O₃ solution (2 mL) were added and the mixture was stirredfor additional 5 min. The organic phase was separated from the aqueousphase and the aqueous phase was further extracted with CH₂Cl₂ (80 mL×3).The combined organic phase was washed with water (10 mL×2), brine (10mL) and dried over Na₂SO₄. After concentration in vacuo, the crudediamine product will be used directly in the next step without furtherpurification.

To an oven-dried 100 mL round bottom flask equipped with a stir bar wasadded the crude diamine product obtained in last step. The flask wasevacuated and backfilled with N₂ twice and then anhydrous CH₂Cl₂ (40 mL)was added. Subsequently, a solution of Boc₂O (546 mg, 2.5 mmol, 0.95equiv) in CH₂Cl₂ (2 mL) was added to the flask at 0° C. within 40 minusing a syringe pump. The mixture was warmed up to room temperature andstirred for additional 1 h (monitored by TLC until the diamine startingmaterial was consumed). Et₃N (0.72 mL, 5.2 mmol, 2.0 equiv), Ac₂O (0.49mL, 5.2 mmol, 2.0 equiv) and a solution of DMAP (25 mg, 0.5 mmol, 0.2equiv) in CH₂Cl₂ (0.5 mL) were added to the above mixture at 0° C. Thereaction mixture was warmed up to room temperature and kept stirring foradditional 2 h until the intermediate was consumed (monitored by TLC).Saturated NaHCO₃ solution (10 mL) was added to quench the reaction. Theorganic phase was separated from the aqueous phase and the aqueous phasewas extracted with CH₂Cl₂ (30 mL×2). The combined organic phase waswashed with brine (10 mL) and dried over Na₂SO₄. After concentration invacuo, the residue was purified through column chromatography(hexanes/EtOAc: from 30:1 to 2:1) to afford the desired product 9 as awhite solid (772 mg, 72% yield over 2 steps, m.p. 141-142° C.).

Ethyl(3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate(9)

[α]_(D) ²⁰=−77° (c 1.06, CHCl₃). IR ν_(max) (neat)/cm⁻¹: 3313 (m), 2971(m), 2932 (m), 1681 (s), 1654 (s), 1544 (m), 1297 (m), 1242 (s), 1051(m), 1013 (m), 943 (m), 733 (m); ¹H NMR (400 MHz, CDCl₃) δ 6.78 (s, 1H),5.89 (d, J=9.0 Hz, 1H), 5.17 (d, J=9.1 Hz, 1H), 4.25-4.15 (m, 2H), 4.06(dd, J=18.5, 9.0 Hz, 1H), 3.97-3.95 (m, 1H), 3.78 (qd, J=9.7, 5.4 Hz,1H), 3.36 (p, J=5.6 Hz, 1H), 2.73 (dd, J=17.8, 5.0 Hz, 1H), 2.43-2.20(m, 1H), 1.97 (s, 3H), 1.62-1.45 (m, 4H), 1.41 (s, 9H), 1.28 (t, J=7.1Hz, 3H), 0.88 (q, J=7.5 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃) δ 170.8,165.9, 156.3, 137.6, 129.3, 82.2, 79.6, 75.8, 60.6, 54.4, 49.0, 30.9,28.3, 26.1, 25.7, 23.4, 14.2, 9.5, 9.2; LRMS (ESI, m/z): calcd forC₂₁H₃₇N₂O₆ ⁺, [M+H⁺], 413.3, found 413.3.

To an oven-dried 10 mL round bottom flask equipped with a stir bar wasadded ethyl(3R,4R,5S)-4-acetamido-5-((tert-butoxycarbonyl)amino)-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate9 (1.21 g, 2.9 mmol). The flask was evacuated and backfilled with N₂twice and then EtOH (4 mL) was added. Subsequently, H₃PO₄ (1.08 mL, 17.6mmol, 6.0 equiv) in EtOH (1.8 mL) was added to the flask at roomtemperature using a syringe. The mixture was warmed up to 78° C. andstirred for additional 12 h (monitored by TLC until the startingmaterial was consumed). The mixture was then cooled to 0° C. and stirredfor 3 h with precipitates generated. The reaction mixture was filteredand the solid was washed with cold acetone (2.0 mL×3). The solid wascollected and dried in vacuo to afford the desired product 10 (Tamiflu)as a white solid (1.0 g, 83% yield, m.p. 188-190° C.).

Ethyl (3R,4R,5S)-4-acetamido-5-amino-3-(pentan-3-yloxy)cyclohex-1-ene-1-carboxylate (oseltamivir phosphate, 10)

[α]_(D) ²⁰=−30° (c 1.01, H₂O). IR ν_(max) (neat)/cm⁻¹: 3347 (m), 3169(br), 2966 (w), 2937 (w), 2874 (w), 1716 (s), 1656 (s), 1549 (s), 1243(s), 1120 (s), 952 (s), 850 (m); ¹H NMR (400 MHz, D₂O) δ 6.75 (s, 1H),4.23 (d, J=9.0 Hz, 1H), 4.15 (dt, J=7.2, 5.3 Hz, 2H), 3.95 (dd, J=11.6,9.0 Hz, 1H), 3.55-3.39 (m, 2H), 2.86 (dd, J=17.0, 5.6 Hz, 1H), 2.50-2.35(m, 1H), 1.98 (s, 3H), 1.41 (ddt, J=41.6, 14.2, 7.2 Hz, 4H), 1.18 (t,J=7.1 Hz, 3H), 0.76 (dt, J=17.7, 7.4 Hz, 6H); ¹³C NMR (100 MHz, D₂O) δ175.2, 167.3, 137.9, 127.5, 84.2, 75.0, 62.3, 52.6, 49.0, 28.1, 25.4,25.0, 22.3, 13.2, 8.5, 8.4; LRMS (ESI, m/z): calcd for C₁₆H₂₉N₂O₄ ⁺,[M−H₃PO₄+H⁺], 313.2, found 313.2.

The compositions and methods of the appended claims are not limited inscope by the specific compositions and methods described herein, whichare intended as illustrations of a few aspects of the claims and anycompositions and methods that are functionally equivalent are intendedto fall within the scope of the claims. Various modifications of thecompositions and methods in addition to those shown and described hereinare intended to fall within the scope of the appended claims. Further,while only certain representative compositions and method stepsdisclosed herein are specifically described, other combinations of thecompositions and method steps also are intended to fall within the scopeof the appended claims, even if not specifically recited. Thus, acombination of steps, elements, components, or constituents may beexplicitly mentioned herein or less, however, other combinations ofsteps, elements, components, and constituents are included, even thoughnot explicitly stated. The term “comprising” and variations thereof asused herein is used synonymously with the term “including” andvariations thereof and are open, non-limiting terms. Although the terms“comprising” and “including” have been used herein to describe variousembodiments, the terms “consisting essentially of” and “consisting of”can be used in place of “comprising” and “including” to provide for morespecific embodiments of the invention and are also disclosed. Other thanin the examples, or where otherwise noted, all numbers expressingquantities of ingredients, reaction conditions, and so forth used in thespecification and claims are to be understood at the very least, and notas an attempt to limit the application of the doctrine of equivalents tothe scope of the claims, to be construed in light of the number ofsignificant digits and ordinary rounding approaches.

What is claimed is:
 1. A method of stereoselectively diazidating acyclohexene compound of Formula (I):

wherein R¹ comprises R^(1a), C(O)R^(1a), C(O)OR^(1a), C(O)N(R^(1a))₂, orSi(R^(1a))₃, wherein R^(1a) is in each case independently selected fromthe group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,aryl, heteroaryl, and C₃₋₈cycloalkyl; wherein R^(h) is hydrogen and R²comprises F, Cl, Br, I, NO₂, CN, OTs, or OMs; R³ is selected fromhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl, comprising contacting the compound of Formula (I) with:a) an iron compound; b) an azide source; c) an activator, wherein theactivator is selected from an iodine (III) compound or a peroxycompound; d) a polydentate ligand; to give a diazido compound of Formula(II):

wherein R^(1′) is selected from R^(1a′), C(O)R^(1a′), C(O)OR^(1a′),C(O)N(R^(1a′))₂, Si(R^(1a′))₃, wherein R^(1a′) is in each caseindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, and C₃₋₈cycloalkyl; whereinR^(h) is hydrogen and R² comprises F, Cl, Br, I, NO₂, CN, OTs, or OMs,or R^(h) and R² together form a double bond.
 2. The method according toclaim 1, wherein the polydentate ligand has the formula:

wherein m is selected from the group consisting of 0, 1, 2, and 3, andin each case R^(LA), R^(LB), R^(LC), and R^(LD) are independentlyselected from the group consisting of R, OR, N(R)₂, PR₃, SiR₃, SR, SO₂R,SO₂N(R)₂, C(O)R; C(O)OR, OCOR; C(O)N(R)₂, OC(O)N(R)₂, N(R)C(O)N(R)₂, F,Cl, Br, I, cyano, and nitro, wherein R is in each case independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, and C₁₋₈heterocyclyl;wherein any two or more of R^(LA), R^(LB), R^(LC), R^(LD), and R maytogether form a ring.
 3. The method according to claim 2, wherein thepolydentate ligand has the formula:

wherein each of R^(7a), R^(7b), R^(8a), and R^(8b) are independentlyselected from the group consisting of R, OR, N(R)₂, PR₃, SiR₃, SR, SO₂R,SO₂N(R)₂, C(O)R; C(O)OR, OCOR; C(O)N(R)₂, OC(O)N(R)₂, N(R)C(O)N(R)₂, F,Cl, Br, I, cyano, and nitro, wherein R is in each case independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈-alkynyl, aryl, C₁₋₈heteroaryl, C₃₋₈cycloalkyl, andC₁₋₈heterocyclyl; wherein any two or more of R^(7a), R^(7b), R^(8a),R^(8b), R^(LD), and R may together form a ring.
 4. The method accordingto claim 2, wherein the polydentate ligand has the formula:


5. The method of claim 1, further comprising converting the compound ofFormula (II) to oseltamivir or a pharmaceutically acceptable saltthereof.
 6. The method of claim 1, further comprising converting thecompound of Formula (II) to a compound of Formula (III):

wherein R^(1″) is selected from R^(1a″), C(O)R^(1a″), C(O)OR^(1a″),C(O)N(R^(1a″))₂, Si(R^(1a″))₃, wherein R^(1a″) is in each caseindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, and heteroaryl, C₃₋₈cycloalkyl.
 7. Themethod of claim 6, further comprising converting the compound of Formula(III) into oseltamivir or a pharmaceutically acceptable salt thereof. 8.The method of claim 6, further comprising converting the compound ofFormula (III) to a compound of Formula (IV):

wherein R⁴, R^(4′), R⁵, and R^(5′) are independently selected fromR^(z), C(O)R^(z), C(O)OR^(z), C(O)N(R^(z))₂, Si(R^(z))₃, wherein R^(z)is in each case independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl; R^(1′″) is selected from R^(1a′″), C(O)R^(1a′″),C(O)OR^(1a′″), C(O)N(R^(1a′″))₂, Si(R^(1a′″))₃, wherein R^(1a′″) is ineach case independently selected from the group consisting of hydrogen,C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl.
 9. The method of claim 8, further comprising convertingthe compound of Formula (IV) into oseltamivir, or a pharmaceuticallyacceptable salt thereof.
 10. The method of claim 1, further comprisingreducing the compound of Formula (II) into the compound of Formula (V):

wherein R⁴, R^(4′), R⁵, and R^(5′) are independently selected fromR^(z), C(O)R^(z), C(O)OR^(z), C(O)N(R^(z))₂, Si(R^(z))₃, wherein R^(z)is in each case independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl.
 11. The method of claim 10, comprising furtherconverting the compound of Formula (V) into oseltamivir, or apharmaceutically acceptable salt thereof.
 12. The method of claim 1,comprising preparing the compound of Formula (I) by cycloadditionbetween a compound of Formula (VI):

and a compound of Formula (VII):

to give the compound of Formula (I).
 13. The method of claim 10, whereinthe compound of Formula (VII) is prepared from a compound of Formula(VIII):

wherein R^(LG) represents a leaving group.
 14. A method comprising a)conducting a cycloaddition reaction to give a cycloaddition product:

wherein R¹ comprises R^(1a), C(O)R^(1a), C(O)OR^(1a), C(O)N(R^(1a))₂, orSi(R^(1a))₃, wherein R^(1a) is in each case independently selected fromthe group consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl,aryl, heteroaryl, and C₃₋₈cycloalkyl; wherein R^(h) is hydrogen and R²comprises F, Cl, Br, I, NO₂, CN, OTs, or OMs; R³ is selected fromhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl; and b) diazidating the cycloaddition product to give acompound of Formula (II):

wherein R^(1′) is selected from R^(1a′), C(O)R^(1a′), C(O)OR^(1a′),C(O)N(R^(1a′))₂, Si(R^(1a′))₃, wherein R^(1a′) is in each caseindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, andC₁₋₈heteroaryl; wherein R^(h) is hydrogen and R² comprises F, Cl, Br, I,NO₂, CN, OTs, or OMs, or R^(h) and R² together form a double bond. 15.The method according to claim 14, comprising further converting thecompound of Formula (II) to oseltamivir, or a pharmaceuticallyacceptable salt thereof.
 16. A method for preparing a compound ofFormula (VIII):

comprising generating in situ the compound of Formula (VII):

from a compound having the formula:

in the presence of a compound of Formula (VI):

wherein R^(LG) is a leaving group; wherein R¹ comprises R^(1a),C(O)R^(1a), C(O)OR^(1a), C(O)N(R^(1a))₂, or Si(R^(1a))₃, wherein R^(1a)is in each case independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈-alkynyl, aryl, heteroaryl, andC₃₋₈cycloalkyl; wherein R^(h) is hydrogen and R² comprises F, Cl, Br, I,NO₂, CN, OTs, or OMs; and R³ is selected from hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, andC₁₋₈heteroaryl.
 17. The method according to claim 16, further comprisingconverting the compound of Formula (VIII) into oseltamivir, or apharmaceutically acceptable salt thereof.
 18. The method according toclaim 17, wherein the compound of Formula (VIII) is racemic and furthercomprising enzymatically resolving the compound of Formula (VIII) toobtain an enantioenriched compound of Formula (VIII-a) and anenantioenriched compound of Formula (IX):


19. The method according to claim 18, comprising further converting thecompound of Formula (VIII-a) into oseltamivir, or a pharmaceuticallyacceptable salt thereof.
 20. A compound having the formula:

wherein R^(1′) is selected from R^(1a′), C(O)R^(1a′), C(O)OR^(1a′),C(O)N(R^(1a′))₂, or Si(R^(1a′))₃, wherein R^(1a′) is in each caseindependently selected from the group consisting of hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl, C₃₋₈cycloalkyl, andC₁₋₈heteroaryl; wherein R^(h) is hydrogen and R² comprises F, Cl, Br, I,NO₂, CN, OTs, or OMs, or R^(h) and R² together form a double bond; andR³ is selected from hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,heteroaryl, and C₃₋₈cycloalkyl.
 21. A method, comprisingenantioselectively deacylating a racemic compound of Formula (VIII):

in the presence of a lipase enzyme and aqueous solvent, to obtain anenantioenriched compound of Formula (VIII-a) and an enantioenrichedcompound of Formula (IX):

wherein R¹ comprises C(O)R^(1a) wherein R^(1a) is selected from thegroup consisting of hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl,heteroaryl, and C₃₋₈cycloalkyl; wherein R^(h) is hydrogen and R²comprises F, Cl, Br, I, NO₂, CN, OTs, or OMs; and R³ is selected fromhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, aryl, heteroaryl,C₃₋₈cycloalkyl, and C₁₋₈heteroaryl.
 22. The method according to claim21, comprising further converting the compound of Formula (VIII-a) intooseltamivir, or a pharmaceutically acceptable salt thereof.